ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels

Juan A. Orellana, Nicolas Froger, Pascal Ezan, Jean X. Jiang, Michael V. L. Bennett, Christian C. Naus, Christian Giaume, Juan C. Sáez

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

Inflammation contributes to neurodegeneration in post-ischemic brain, diabetes, and Alzheimer's disease. Participants in this inflammatory response include activation of microglia and astrocytes. We studied the role of microglia treated with amyloid-β peptide (Aβ) on hemichannel activity of astrocytes subjected to hypoxia in high glucose. Reoxygenation after 3 h hypoxia in high glucose induced transient astroglial permeabilization via Cx43 hemichannels and reduction in intercellular communication via Cx43 cell-cell channels. Both responses were greater and longer lasting in astrocytes previously exposed for 24 h to conditioned medium from Aβ-treated microglia (CM-Aβ). The effects of CM-Aβ were mimicked by TNF-α and IL-1β and were abrogated by neutralizing TNF-α with soluble receptor and IL-1β with a receptor antagonist. Astrocytes under basal conditions protected neurons against hypoxia, but exposure to CM-Aβ made them toxic to neurons subjected to a sub-lethal hypoxia/reoxygenation episode, revealing the additive nature of the insults. Astrocytes exposed to CM-Aβ induced permeabilization of cortical neurons through activation of neuronal pannexin 1 (Panx1) hemichannels by ATP and glutamate released through astroglial Cx43 hemichannels. In agreement, inhibition of NMDA or P2X receptors only partially reduced the activation of neuronal Panx1 hemichannels and neuronal mortality, but simultaneous inhibition of both receptors completely prevented the neurotoxic response. Therefore, we suggest that responses to ATP and glutamate converge in activation of neuronal Panx1 hemichannels. Thus, we propose that blocking hemichannels expressed by astrocytes and/or neurons in the inflamed nervous system could represent a novel and alternative strategy to reduce neuronal loss in various pathological states including Alzheimer's disease, diabetes and ischemia.

Original languageEnglish (US)
Pages (from-to)826-840
Number of pages15
JournalJournal of Neurochemistry
Volume118
Issue number5
DOIs
StatePublished - Sep 2011

Fingerprint

Connexin 43
Astrocytes
Glutamic Acid
Adenosine Triphosphate
Chemical activation
Neurons
Microglia
Medical problems
Alzheimer Disease
Glucose
Interleukin-1 Receptors
Poisons
Neurology
Brain Diseases
N-Methylaspartate
Conditioned Culture Medium
Interleukin-1
Amyloid
Nervous System
Brain

Keywords

  • Alzheimer's disease
  • amyloid β-peptide
  • connexin
  • cytokines
  • diabetes mellitus
  • gap junctions
  • pannexin
  • stroke

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. / Orellana, Juan A.; Froger, Nicolas; Ezan, Pascal; Jiang, Jean X.; Bennett, Michael V. L.; Naus, Christian C.; Giaume, Christian; Sáez, Juan C.

In: Journal of Neurochemistry, Vol. 118, No. 5, 09.2011, p. 826-840.

Research output: Contribution to journalArticle

Orellana, Juan A. ; Froger, Nicolas ; Ezan, Pascal ; Jiang, Jean X. ; Bennett, Michael V. L. ; Naus, Christian C. ; Giaume, Christian ; Sáez, Juan C. / ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. In: Journal of Neurochemistry. 2011 ; Vol. 118, No. 5. pp. 826-840.
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